The mechanism for reduced expression of NNMT and its relation to HCC progression is not clear. Several metallothionein genes involved in detoxification and drug metabolism are downregulated in HCC especially in tumors with high Edmonson grades, reflecting de-differentiation of cancer cells [12]. Thus, it is possible that the liver specific function of NNMT is lost during the progression of HCC. On the other hand, a recent in vitro study found that NNMT was necessary for cancer TGF-beta/Smad inhibitor cell migration in Ipatasertib bladder cancer cell lines [24], pointing to a possible involvement in tumor invasion.

In 120 HCCs observed in this study, NNMT mRNA was higher in recurrent tumors than in non-recurrent tumors especially in stage III & IV tumors, although the differences were not statistically significant. Thus, there’s a possibility that increased NNMT expression is related to cell mobility and tumor invasiveness in high stage HCC. Interestingly, the NNMT expression level was decreased in stage II tumors Selleckchem Quizartinib compared

to stage I tumors, while stage III & IV tumors showed a similar NNMT level as stage I tumors. This could be due to tumor de-differentiation preceding tumor invasion. However, we cannot rule out other regulatory mechanisms independent of tumor de-differentiation and invasion. In tumors, abnormal expression of NNMT has been reported in glioblastoma [25], stomach cancer [26, 27], papillary thyroid cancer [28, 29], colon cancer [30], and renal carcinoma [31, 32]. NNMT was identified as a novel serum marker for human colorectal cancers although this protein is not thought to be secreted [30]. Interestingly, the upregulation of NNMT was RVX-208 found to be inversely correlated with tumor size in renal clear cell carcinoma, suggesting that the enzyme

may be significant in an initial phase of malignant conversion [32]. Increased expression of NNMT in non-tumor cells was reported in a few situations: the cerebellum of patients with Parkinson’s disease [33, 34], human hepatoma cells (Huh7) with expression of the hepatitis C core protein [35], and the liver of mice transplanted with tumors [36, 37]. In these situations, the mechanism for deregulated NNMT expression remains unclear. Recently, NNMT promoter was cloned and studied in papillary thyroid cancer cell lines, where it was shown to be activated by hepatocyte nuclear factor-1β [29]. Subsequently, it was found that the NNMT promoter region also contains the consensus sequences for signal transducers and activators of transcription (STAT) binding elements and nuclear factor-interleukin (IL) 6 binding elements [38]. Accordingly, hepatoma cell line (Hep-G2), which expressed low levels of NNMT, increased NNMT expression several fold upon stimulation by IL-6. The stimulation by IL-6 was largely abolished with the expression of dominant-negative STAT3 [38]. Activation of STAT3 alone caused a four-fold higher induction of NNMT promoter activity in the transformed Hep-G2 cells.